This program is broadly directed toward establishing a paradigm within the SPORE program for the development of targeted, mechanism-based, molecular therapeutics for the treatment of prostate cancer. The specific goal of the proposal is the basic study and preclinical and clinical development of the ansamycin antibiotics as drugs which inhibit pathways important for the growth of advanced disease. The program involves chemists, cell and molecular biologist, pathologists and clinicians at the Center. Ansamycins are a novel class of anti-tumor antibiotics that bind hsp90 and cause the degradation of several key signaling molecules, including androgen receptor and HER2, and the inactivation of the Akt kinase signaling pathway. These properties suggest that ansamycins may be useful in the treatment of advanced prostate cancer. We have shown that ansamycins lead to the Rb-dependent G1 arrest of cancer cells, followed by apoptosis and that they have antitumor activity in animal models of prostate cancer at doses that are tolerable to the host. These findings led to an NCI-initiated phase I trial of 17allylarninogeldanamycin (17-AAG in which we are taking part. This grant proposes a phase II trial of 1 7-AAG based on our preclinical and phase I data, describes further in vitro and animal studies on the mechanism of action of 1 7-AAG alone and in combination with other agents, and phase I/II trials based on these preclinical studies. This work is the result of close, bidirectional interactions between the basic and clinical scientists at MSKCC which will serve as a model for the development of other modalities.